The DNA-binding protein CTCF limits proximal V? recombination and restricts ? enhancer interactions to the immunoglobulin ? light chain locus.

Regulation of immunoglobulin (Ig) V(D)J gene rearrangement is dependent on higher-order chromatin organization. Here, we studied the in vivo function of the DNA-binding zinc-finger protein CTCF, which regulates interactions between enhancers and promoters. By conditional deletion of the Ctcf gene in the B cell lineage, we demonstrate that loss of CTCF allowed Ig heavy chain recombination, but pre-B cell proliferation and differentiation was severely impaired. In the absence of CTCF, the Ig? light chain locus showed increased proximal and reduced distal V? usage. This was associated with enhanced proximal V? and reduced J? germline transcription. Chromosome conformation capture experiments demonstrated that CTCF limits interactions of the Ig? enhancers with the proximal V(?) gene region and prevents inappropriate interactions between these strong enhancers and elements outside the Ig? locus. Thus, although Ig gene recombination can occur in the absence of CTCF, it is a critical factor determining V? segment choice for recombination.